Implantable Device For Evaluating Autonomic Cardiovascular Drive In A Patient Suffering From Chronic Cardiac Dysfunction

ABSTRACT

An implantable device for evaluating autonomic cardiovascular drive in a patient suffering from chronic cardiac dysfunction is provided. A stimulation therapy lead includes helical electrodes configured to conform to an outer diameter of a cervical vagus nerve sheath, and a set of connector pins electrically connected to the helical electrodes. A neurostimulator includes an electrical receptacle into which the connector pins are securely and electrically coupled. The neurostimulator also includes a pulse generator configured to therapeutically stimulate the vagus nerve through the helical electrodes in alternating cycles of stimuli application and stimuli inhibition that are tuned to both efferently activate the heart&#39;s intrinsic nervous system and afferently activate the patient&#39;s central reflexes by triggering bi-directional action potentials. The neurostimulator includes a recordable memory storing a baseline heart rate. The neurostimulator includes an integrated leadless heart rate sensor configured to continually monitor heart rate in light of the baseline heart rate.

FIELD

This application relates in general to chronic cardiac dysfunctiontherapy and, in particular, to an implantable device for evaluatingautonomic cardiovascular drive in a patient suffering from chroniccardiac dysfunction.

BACKGROUND

Congestive heart failure (CHF) is a progressive and physicallydebilitating chronic medical condition in which the heart is unable tosupply sufficient blood flow to meet the body's needs. CHF is a form ofchronic cardiac dysfunction that affects nearly five million people eachyear in the United States alone and continues to be the leading cause ofhospitalization for persons over the age of 65. CHF requires seekingtimely medical attention.

Pathologically, CHF is characterized by an elevated neuroexitatory statethat is accompanied by impaired arterial and cardiopulmonary baroreflexfunction and reduced vagal activity. CHF is initiated by cardiacdysfunction, which triggers compensatory activations of thesympathoadrenal (sympathetic) nervous and therenin-angiotensin-aldosterone hormonal systems. Initially, these twomechanisms help the heart to compensate for deteriorating pumpingfunction. Over time, however, overdriven sympathetic activation andincreased heart rate promote progressive left ventricular dysfunctionand remodeling, and ultimately foretell poor long term patient outcome.

Anatomically, the heart is innervated by sympathetic and parasympatheticnerves originating through the vagus nerve and arising from the body'scervical and upper thoracic regions. The sympathetic and parasympatheticnervous systems, though separate aspects of the autonomous nervoussystem, dynamically interact thorough signals partially modulated bycAMP and cGMP secondary messengers. When in balance, each nervous systemcan presynaptically inhibit the activation of the other nervous system'snerve traffic. During CHF, however, the body suffers an autonomicimbalance of these two nervous systems, which leads to cardiacarrhythmogenesis, progressively worsening cardiac function, and eventualmortality.

Currently, the standard of care for managing chronic cardiacdysfunction, such as CHF, includes prescribing medication and mandatingchanges to a patient's diet and lifestyle, to counteract cardiacdysfunction. These medications include diuretics, angiotensin-convertingenzyme inhibitors, angiotensin receptor blockers, beta-blockers, andaldosterone antagonists, which cause vasodilation, reduce secretion ofvasopressin, reduce production and secretion of aldosterone, lowerarteriolar resistance, increase venous capacity, increase cardiacoutput, index and volume, lower renovascular resistance, and lead toincreased natriuresis, among other effects. The effectiveness of thesemedications is palliative, but not curative. Moreover, patients oftensuffer side effects and comorbidities, such as pulmonary edema, sleepapnea, and myocardial ischemia. Re-titration of drug therapy followingcrisis may be required, and neither continued drug efficacy nor patientsurvival are assured.

More recently, cardiac resynchronization therapy (CRT) has becomeavailable to patients presenting with impairment of systolic function,such as is caused by an intraventricular conduction delay orbundle-branch block that forces the heart's ventricles to contractdyssynchronously. Typically, implantable CRT devices use a set ofbiventricular leads to stimulate both the ventricular septum and thelateral wall of the left ventricle. CRT restores the synchronous beatingof the heart through coordinated pacing of both ventricles. However, CRTis only helpful for treating systolic dysfunction and is not indicatedfor patients presenting with preserved ejection fraction. Thus, CRT islimited to patients exhibiting a wide QRS complex and mechanicaldyssynchrony, whereas patients presenting with systolic dysfunction orimpaired ejection fraction and a narrow QRS have limited therapeuticoptions.

Medication and CRT are only partial solutions to managing chroniccardiac dysfunction, and neural stimulation has been proposed as analternative way to treat chronic cardiac dysfunction conditions, such asCHF, by correcting the underlying autonomic imbalance of the sympatheticand parasympathetic nervous systems. The heart contains an intrinsicnervous system that includes spatially-distributed sensory afferentneurons, interconnecting local circuit neurons, and motor adrenergic andcholinergic efferent neurons. Peripheral cell stations of these neuronsactivate under the tonic influence of spinal cord and medullary reflexesand circulating catecholamines to influence overlapping regions of theheart. Suppression of excessive neural activation by electricallymodulating select vagal nerve fibers may help improve the heart'smechanical function as well as to reduce the heart's intrinsic nervoussystem's propensity to induce atrial arrhythmias during autonomicimbalance.

Electrical vagus nerve stimulation (VNS) is currently used clinicallyfor the treatment of drug-refractory epilepsy and depression, and isunder investigation for applications in Alzheimer's disease, anxiety,heart failure, inflammatory disease, and obesity. In particular, vagusnerve stimulation has been proposed as a long-term therapy for thetreatment of CHF, as described in Sabbah et al., “Vagus NerveStimulation in Experimental Heart Failure,” Heart Fail. Rev., 16:171-178(2011), the disclosure of which is incorporated by reference. The Sabbahpaper discusses canine studies using a vagus stimulation device,manufactured by BioControl Medical Ltd., Yehud, Israel, which includes asignal generator, right ventricular sensing lead, and right vagus nervecuff stimulation lead. The sensing leads enable stimulation of the rightvagus nerve to be synchronized to the cardiac cycle through feedbackon-demand heart rate control. A bipolar nerve cuff electrode wassurgically implanted on the right vagus nerve at the mid-cervicalposition. Electrical stimulation to the right cervical vagus nerve wasdelivered only when heart rate increased beyond a preset level to reducebasal heart rate by ten percent. Self-titration using “magnet mode” wasimpracticable in light of the test subject, here canine. Stimulation wasprovided at an impulse rate and intensity intended to keep the heartrate within a desired range by preferential stimulation of efferentnerve fibers leading to the heart while blocking afferent neuralimpulses to the brain. An asymmetric bi-polar multi-contact cuffelectrode was employed to provide cathodic induction of actionpotentials while simultaneously applying asymmetric anodal blocks thatwere expected to lead to preferential, but not exclusive, activation ofvagal efferent fibers. Although effective in restoring baroreflexsensitivity and, in the canine model, significantly increasing leftventricular ejection fraction and decreasing left ventricular enddiastolic and end systolic volumes, restoration of autonomic balance wasleft unaddressed.

Other uses of electrical nerve stimulation for therapeutic treatment ofvarious physiological conditions are described. For instance, U.S. Pat.No. 6,600,954, issued Jul. 29, 2003 to Cohen et al. discloses a methodand apparatus for selective control of nerve fibers. At least oneelectrode device is applied to a nerve bundle capable, upon activation,of generating unidirectional action potentials to be propagated throughboth small diameter and large diameter sensory fibers in the nervebundle, and away from the central nervous system. The device isparticularly useful for reducing pain sensations, such as propagatingthrough the legs and arms.

U.S. Pat. No. 6,684,105, issued Jan. 27, 2004 to Cohen et al. disclosesan apparatus for treatment of disorders by unidirectional nervestimulation. An apparatus for treating a specific condition includes aset of one or more electrode devices that are applied to selected sitesof the central or peripheral nervous system of the patient. For someapplications, a signal is applied to a nerve, such as the vagus nerve,to stimulate efferent fibers and treat motility disorders, or to aportion of the vagus nerve innervating the stomach to produce asensation of satiety or hunger. For other applications, a signal isapplied to the vagus nerve to modulate electrical activity in the brainand rouse a comatose patient, or to treat epilepsy and involuntarymovement disorders.

U.S. Pat. No. 7,123,961, issued Oct. 17, 2006 to Kroll et al. disclosesstimulation of autonomic nerves. An autonomic nerve is stimulated toaffect cardiac function using a stimulation device in electricalcommunication with the heart by way of three leads suitable fordelivering multi-chamber stimulation and shock therapy. In addition, thedevice includes a fourth lead having three electrodes positioned in ornear the heart, or near an autonomic nerve remote from the heart. Poweris delivered to the electrodes at a set power level. The power isdelivered at a reduced level if cardiac function was affected.

U.S. Pat. No. 7,225,017, issued May 29, 2007 to Shelchuk disclosesterminating ventricular tachycardia. Cardioversion stimulation isdelivered upon detecting a ventricular tachycardia. A stimulation pulseis delivered to a lead having one or more electrodes positionedproximate to a parasympathetic pathway. Optionally, the stimulationpulse is delivered post inspiration or during a refractory period tocause a release of acetylcholine.

U.S. Pat. No. 7,277,761, issued Oct. 2, 2007 to Shelchuk discloses vagalstimulation for improving cardiac function in heart failure or CHFpatients. An autonomic nerve is stimulated to affect cardiac functionusing a stimulation device in electrical communication with the heart byway of three leads suitable for delivering multi-chamber stimulation andshock therapy. In addition, the device includes a fourth lead havingthree electrodes positioned in or near the heart, or near an autonomicnerve remote from the heart. A need for increased cardiac output isdetected and a stimulation pulse is delivered through an electrode, forexample, proximate to the left vagosympathetic trunk or branch tothereby stimulate a parasympathetic nerve. If the stimulation has causedsufficient increase in cardiac output, ventricular pacing may then beinitiated at an appropriate reduced rate.

U.S. Pat. No. 7,295,881, issued Nov. 13, 2007 to Cohen et al. disclosesnerve branch-specific action potential activation, inhibition andmonitoring. Two preferably unidirectional electrode configurations flanka nerve junction from which a preselected nerve branch issues,proximally and distally to the junction, with respect to the brain.Selective nerve branch stimulation can be used in conjunction withnerve-branch specific stimulation to achieve selective stimulation of aspecific range of fiber diameters, substantially restricted to apreselected nerve branch, including heart rate control, where activatingonly the vagal B nerve fibers in the heart, and not vagal A nerve fibersthat innervate other muscles, can be desirous.

U.S. Pat. No. 7,778,703, issued Aug. 17, 2010 to Gross et al. disclosesselective nerve fiber stimulation for treating heart conditions. Anelectrode device is adapted to be coupled to a vagus nerve of a subjectand a control unit drives the electrode device by applying to the vagusnerve a stimulating current and also an inhibiting current, which arecapable of respectively inducing action potentials in a therapeuticdirection in a first set and a second set of nerve fibers in the vagusnerve and inhibiting action potentials in the therapeutic direction inthe second set of nerve fibers only. The nerve fibers in the second sethave larger diameters than the nerve fibers in the first set. Thecontrol unit typically drives the electrode device to apply signals tothe vagus nerve to induce the propagation of efferent action potentialstowards the heart and suppress artificially-induced afferent actionpotentials toward the brain.

U.S. Pat. No. 7,813,805, issued Oct. 12, 2010 to Farazi and U.S. Pat.No. 7,869,869, issued Jan. 11, 2011 to Farazi both disclose subcardiacthreshold vagal nerve stimulation. A vagal nerve stimulator isconfigured to generate electrical pulses below a cardiac threshold ofthe heart, which are transmitted to a vagal nerve, so as to inhibit orreduce injury resulting from ischemia. The cardiac threshold is athreshold for energy delivered to the heart above which there is aslowing of the heart rate or conduction velocity. In operation, thevagal nerve stimulator generates the electrical pulses below the cardiacthreshold, such that heart rate is not affected.

Finally, U.S. Pat. No. 7,885,709, issued Feb. 8, 2011 to Ben-Daviddiscloses nerve stimulation for treating disorders. A control unit canbe configured to drive an electrode device to stimulate the vagus nerve,so as to modify heart rate variability, or to reduce heart rate, bysuppressing the adrenergic (sympathetic) system. The vagal stimulationreduces the release of catecholamines in the heart, thereby loweringadrenergic tone at its source. For some applications, the control unitsynchronizes the stimulation with the subject's cardiac cycle, while forother applications, the stimulation can be applied, for example, in aseries of pulses. To reduce heart rate, stimulation is applied using atarget heart rate lower than the subject's normal average heart rate.

Accordingly, a need remains for an approach to therapeutically treatingchronic cardiac dysfunction, including CHF, through a form of electricalstimulation of the cervical vagus nerve to confirm pre-therapeuticcardiovascular drive and subsequently restore autonomic balance.

SUMMARY

Excessive sustained activation of the sympathetic nervous system has adeleterious effect on long term cardiac performance and ultimately onthe survival of chronic cardiac dysfunction patients. Bi-directionalafferent and efferent neural stimulation through the vagus nerve canbeneficially restore autonomic balance and improve long term patientoutcome. Stimulus delivery can be provided through a vagalneurostimulator per a schedule specified in stored stimulationparameters or based on sensory-based therapy triggers provided throughan integrated heart rate sensor.

One embodiment provides a vagus nerve neurostimulator for evaluatingautonomic cardiovascular drive. An implantable neurostimulator includesa pulse generator configured to drive electrical therapeutic stimulationtuned to restore autonomic balance through electrical pulsescontinuously and periodically delivered in both afferent and efferentdirections of the cervical vagus nerve through a pair of helicalelectrodes via an electrically coupled nerve stimulation therapy lead.The implantable neurostimulator also includes a leadless heart ratesensor configured to continually monitor heart rate against a storedbaseline heart rate.

A further embodiment provides an implantable device for evaluatingautonomic cardiovascular drive. An implantable neurostimulator deviceincludes a pulse generator configured to deliver both afferent andefferent therapeutic electrical stimulation to a cervical vagus nerve incontinuous alternating cycles of stimuli application and stimuliinhibition. A cervical vagus nerve stimulation therapy lead iselectrically coupled to the pulse generator and is terminated by a pairof helical electrodes through which the therapeutic electricalstimulation is delivered to the cervical vagus nerve. An integratedleadless heart rate sensor configured to continually monitor heart rateagainst a baseline heart rate stored in a memory in the pulse generator.

A still further embodiment provides an implantable device for evaluatingautonomic cardiovascular drive in a patient suffering from chroniccardiac dysfunction. A cervical vagus nerve stimulation therapy leadincludes a pair of helical electrodes configured to conform to an outerdiameter of a cervical vagus nerve sheath of a patient and a set ofconnector pins electrically connected to the helical electrodes by aninsulated electrical lead body. A neurostimulator is powered by aprimary battery and enclosed in a hermetically sealed housing. Theneurostimulator includes an electrical receptacle included on an outersurface of the housing into which the connector pins are securely andelectrically coupled. The neurostimulator also includes a pulsegenerator configured to therapeutically stimulate the cervical vagusnerve through the helical electrodes in alternating cycles of stimuliapplication and stimuli inhibition that are tuned to both efferentlyactivate the heart's intrinsic nervous system and afferently activatethe patient's central reflexes by triggering bi-directional actionpotentials. The neurostimulator further includes a recordable memorywithin which is stored a baseline heart rate for the patient prior tostimulation therapy initiation. Finally, the neurostimulator includes anintegrated leadless heart rate sensor configured to continually monitorthe patient's heart rate in light of the baseline heart rate.

By restoring autonomic balance, therapeutic VNS operates acutely todecrease heart rate, increase heart rate variability and coronary flow,reduce cardiac workload through vasodilation, and improve leftventricular relaxation. Over the long term, VNS provides the chronicbenefits of decreased negative cytokine production, increased baroreflexsensitivity, increased respiratory gas exchange efficiency, favorablegene expression, renin-angiotensin-aldosterone system down-regulation,and anti-arrhythmic, anti-apoptotic, and ectopy-reducinganti-inflammatory effects.

Still other embodiments of the present invention will become readilyapparent to those skilled in the art from the following detaileddescription, wherein are described embodiments by way of illustratingthe best mode contemplated for carrying out the invention. As will berealized, the invention is capable of other and different embodimentsand its several details are capable of modifications in various obviousrespects, all without departing from the spirit and the scope of thepresent invention. Accordingly, the drawings and detailed descriptionare to be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patient,in accordance with one embodiment.

FIG. 2 is a diagram showing the implantable neurostimulator andsimulation therapy lead of FIG. 1 with the therapy lead unplugged.

FIG. 3 is a diagram showing an external programmer for use with theimplantable neurostimulator of FIG. 1.

FIG. 4 is a diagram showing the helical electrodes provided as on thestimulation therapy lead of FIG. 2 in place on a vagus nerve in situ.

FIG. 5 is a graph showing, by way of example, the relationship betweenthe targeted therapeutic efficacy and the extent of potential sideeffects resulting from use of the implantable neurostimulator of FIG. 1.

FIG. 6 is a graph showing, by way of example, the optimal duty cyclerange based on the intersection depicted in FIG. 5.

FIG. 7 is a timing diagram showing, by way of example, a stimulationcycle and an inhibition cycle of VNS as provided by implantableneurostimulator of FIG. 1.

DETAILED DESCRIPTION

The sympathetic nervous system affects cardiovascular physiology in an“all-or-nothing” form of neurological response, whereas theparasympathetic nervous system selectively modulates specific regions ofthe heart at various levels of activation. Through these two nervoussystems, the autonomic nervous system directly controls the heart byaffecting conduction, refractoriness, impulse formation, and theelectrophysiological properties of the cardiac tissue, and indirectly byinfluencing the heart's homodynamics, blood flow, and metabolism, aswell as exercising control over other body functions that rely on theheart.

The sympathetic and parasympathetic nervous systems dynamically interactthorough signals partially modulated by cAMP and cGMP secondarymessengers to presynaptically influence the activation of each other'snerve traffic. Changes to one nervous system can indirectly affect nerveactivation in the other. For instance, during autonomic imbalance,sympathetic neural activity increases while cardiac vagal activation,and therefore sympathetic innervation, is withdrawn. In view of theircollaborative influence over cardiac function, the restoration ofautonomic balance between these nervous systems is crucial to managingchronic cardiac dysfunction.

Conventional therapeutic alteration of cardiac vagal efferent activationthrough electrical stimulation of sympathetic vagal nerve fibers canproduce beneficial bradycardia and modification in atrial andventricular contractile function. However, such targeting of only theefferent nerves of the sympathetic nervous system is clinicallyinsufficient to restore autonomic balance, as any affect onparasympathetic activation merely occurs due to incidental recruitmentof parasympathetic nerve fibers. In contrast, propagating bi-directionalaction potentials through parasympathetic afferent and efferent nervefibers in the vagus nerve resulting from neural stimulation engages bothmedullary and cardiac reflex control components and works to directlyrestore autonomic balance by engaging both components of both nervoussystems. Moreover, many of the conventional approaches to VNS monitorheart rate through an intracardiac lead, typically implanted into theright ventricle and adapted from sensing leads used in pacemakers anddefibrillators. Implantation of these leads is surgically complex andincreases risk of injury to the patient and post-surgical complications.

An implantable vagus nerve stimulator with integrated heart rate sensor,such as used to treat drug-refractory epilepsy and depression, can beadapted to use in managing chronic cardiac dysfunction throughtherapeutic bi-directional vagal stimulation. In addition, an integratedheart rate sensor can allow the patient's heart rate to be determinedprior to the initiation of therapy delivery, or the heart rate can beprovided to the stimulator from an external source. FIG. 1 is a frontanatomical diagram showing, by way of example, placement of animplantable vagus stimulation device 11 in a male patient 10, inaccordance with one embodiment. The VNS provided through the stimulationdevice 11 operates under several mechanisms of action. These mechanismsinclude increasing parasympathetic outflow and inhibiting sympatheticeffects by blocking norepinephrine release. More importantly, VNStriggers the release of acetylcholine (ACh) into the synaptic cleft,which has beneficial anti-arrhythmic, anti-apoptotic, andectopy-reducing anti-inflammatory effects.

The implantable vagus stimulation device 11 includes three maincomponents, an implantable neurostimulator 12, a therapy lead 13, andhelical electrodes 14. In addition, the operation of the neurostimulator12 can be remotely checked, downloaded, diagnosed, and programmed byhealthcare professionals using an external programmer (as furtherdescribed below with reference to FIG. 3). Together, the implantablevagus stimulation device 11 and the external programmer form a VNStherapeutic delivery system.

The neurostimulator 12 is implanted in the patient's right or leftpectoral region generally on the same side of the patient's body as thevagus nerve 15, 16 to be stimulated. A subcutaneous pocket is formed inthe subclavicular region into which the neurostimulator 12 is placed.The helical electrodes 14 are generally implanted on the vagus nerve 15,16 about halfway between the clavicle 19 a-b and the mastoid process.The therapy lead 13 and helical electrodes 14 are implanted by firstexposing the carotid sheath and chosen vagus nerve 15, 16 through alatero-cervical incision on the ipsilateral side of the patient's neck18. The helical electrodes 14 are then placed onto the exposed nervesheath and tethered. A subcutaneous tunnel is formed between therespective implantation sites of the neurostimulator 12 and helicalelectrodes 14, through which the therapy lead 13 is guided to theneurostimulator 12 and securely connected.

Anatomically, the vagus nerve includes a pair of nerve fiber bundles 15,16 that both proceed laterally through the neck, thorax, and abdomen,and distally innervate the heart 17 and other major organs and bodytissue. The stimulation device 11 bi-directionally stimulates the vagusnerve 15, 16 through application of continuous, periodic electricalstimuli. Both sympathetic and parasympathetic nerve fibers arestimulated through the helical electrodes 14 of the stimulation device11. Stimulation of the cervical vagus nerve results in propagation ofaction potentials in both afferent and efferent directions from the siteof stimulation. Afferent action potentials propagate toward theparasympathetic nervous system's origin in the medulla in the nucleusambiguus, nucleus tractus solitarius, and the dorsal motor nucleus, aswell as towards the sympathetic nervous system's origin in theintermediolateral cell column of the spinal cord.

Efferent action potentials propagate toward the heart to innervate thecomponents of the heart's intrinsic nervous system. Intracardially, thecardiac nervous system is conceived as two major outflow branchesexerting reciprocal control over cardiac indices under sole influence ofcentral neuronal command. The outflow branches respectively regulateadrenergic (sympathetic) and cholinergic (parasympathetic) efferentpreganglionic neuronal activity. Innervation of the heart 17 isregionalized and exhibits a high degree of asymmetry. Within the heart17, the greatest concentration of vagal nerves is found first in thesinus node and then in the atrioventricular node. Cardiac efferents ofthe left vagus nerve 15 regulate cardiac contractility through theirinfluence on conduction in the atrioventricular (AV) node. Cardiacefferents of the right vagus nerve 16 affect sinus node automaticity andregulate heart rate. Thus, right-sided cervical vagal stimulation tendsto produce sinus bradycardia, whereas left-sided cervical vagalstimulation tends to produce AV nodal blockage.

Either the left or right vagus nerve 15, 16 can be stimulated by thestimulation device 11, although stimulation of the left vagus nerve 15is preferred because stimulation of the left vagus nerve 15 is lesslikely to be arrhythmogenic. The left vagus nerve 15 has fewerprojections to the sinoatrial node and is therefore less likely toseverely reduce heart rate. Left VNS increases AV nodal conduction timeand refractory period. In current form, VNS elicits bi-directionalactivation of both afferent and efferent nerve fibers. The balancebetween achieving therapeutic benefits (afferent) and side-effects(efferent) is largely determined by the threshold differences betweenactivation of the different vagus nerve fibers.

The VNS therapy is autonomously delivered to the patient's vagus nerve15, 16 through three implanted components, a neurostimulator 12, therapylead 13, and helical electrodes 14. FIG. 2 is a diagram showing theimplantable neurostimulator 12 and simulation therapy lead 13 of FIG. 1with the therapy lead unplugged 20. In one embodiment, theneurostimulator 12 can be adapted from a VNS Therapy AspireSR Model 106generator, manufactured and sold by Cyberonics, Inc., Houston, Tex.,although other manufactures and types of single-pin receptacleimplantable VNS neurostimulators with integrated leadless heart ratesensors could also be used. The stimulation therapy lead 13 and helicalelectrodes 14 are generally fabricated as a combined assembly and can beadapted from a Model 302 lead, PerenniaDURA Model 303 lead, orPerenniaFLEX Model 304 lead, all of which are also manufactured and soldby Cyberonics, Inc., in two sizes based on helical electrode innerdiameter, although other manufactures and types of single-pinreceptacle-compatible therapy leads and electrodes could also be used.

The neurostimulator 12 provides continuous alternating ON-OFF cycles ofvagal stimulation that when applied to the vagus nerve through theelectrodes 14, produce action potentials in the underlying nerves thatpropagate bi-directionally; afferently propagating action potentialsactivate the medial medullary sites responsible for central reflexcontrol and efferently propagating action potentials activate theheart's intrinsic nervous system. Cardiac motor neurons, when activated,influence heart rate, AV nodal conduction, and atrial and ventricularinotropy, thereby providing chronic cardiac dysfunction therapeuticeffects. In addition, the alternating cycles can be tuned to activatephasic parasympathetic response in the vagus nerve 15, 16 beingstimulated by bi-directionally modulating vagal tone.

The neurostimulator 12 includes an electrical pulse generator thatdrives electrical therapeutic stimulation, which is tuned to restoreautonomic balance, through electrical pulses that are continuously andperiodically delivered in both afferent and efferent directions of thevagus nerve 15, 16. The neurostimulator 12 is enclosed in a hermeticallysealed housing 21 constructed of a biocompatible, implantation-safematerial, such as titanium. The housing 21 contains electronic circuitry22 powered by a primary battery 22, such as a lithium carbonmonoflouride battery. The electronic circuitry 22 is implemented usingcomplementary metal oxide semiconductor integrated circuits that includea microprocessor that executes a control program according to the storedstimulation parameters as programmed into the neurostimulator 12; avoltage regulator that regulates system power; logic and controlcircuitry, including a recordable memory 29 within which the stimulationparameters are stored, that controls overall pulse generator function,receives and implements programming commands from the externalprogrammer, or other external source, and collects and stores telemetryinformation, processes sensory input, and controls scheduled andsensory-based therapy outputs; a transceiver that remotely communicateswith the external programmer using radio frequency signals; an antenna,which receives programming instructions and transmits the telemetryinformation to the external programmer; and a reed switch 30 thatprovides a manually-actuatable mechanism to place the neurostimulatorinto an on-demand stimulation mode or to inhibit stimulation, also knownas “magnet mode.” Other electronic circuitry and components, such as anintegrated heart rate sensor, are possible.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22, particularly the logic and control circuitry, whichcontrol stimulus delivery per a schedule specified in the storedstimulation parameters, based on sensory-based therapy triggers (asfurther described infra) or on-demand in response to magnet mode, aprogramming wand instruction, or other external source. The storedstimulation parameters are programmable (as further described below withreference to FIG. 7). In addition, sets of pre-selected stimulationparameters can be provided to physicians through the external programmerand fine-tuned to a patient's physiological requirements prior to beingprogrammed into the neurostimulator 12, such as described incommonly-assigned U.S. patent application, entitled“Computer-Implemented System and Method for Selecting Therapy Profilesof Electrical Stimulation of Cervical Vagus Nerves for Treatment ofChronic Cardiac Dysfunction,” Ser. No. ______, filed on Dec. 7, 2011,pending, the disclosure of which is incorporated by reference. Themagnet mode can be used by the patient 10 to exercise on-demand manualcontrol over the therapy delivery and titration of the neurostimulator,such as described in commonly-assigned U.S. patent application, entitled“Implantable Device for Facilitating Control of Electrical Stimulationof Cervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction,”Ser. No. ______, filed on Dec. 7, 2011, pending, the disclosure of whichis incorporated by reference. The stimulation parameters also includethe levels of stimulation for the bi-directional action potentials.

Externally, the neurostimulator 12 includes a header 24 to securelyreceive and connect to the therapy lead 13. In one embodiment, theheader 24 encloses a receptacle 25 into which a single pin for thetherapy lead 13 can be received, although two or more receptacles couldalso be provided, along with the requisite additional electroniccircuitry 22. The header 24 internally includes a lead connector block(not shown) and a set of set screws 26.

The therapy lead 13 delivers an electrical signal from theneurostimulator 12 to the vagus nerve 15, 16 via the helical electrodes14. On a proximal end, the therapy lead 13 has a lead connector 27 thattransitions an insulated electrical lead body to a metal connector pin28. During implantation, the connector pin 28 is guided through thereceptacle 25 into the header 24 and securely fastened in place usingthe set screws 26 to electrically couple the therapy lead 13 to theneurostimulator 12. On a distal end, the therapy lead 13 terminates withthe helical electrode 14, which bifurcates into a pair of anodic andcathodic electrodes 62 (as further described below with reference toFIG. 4). In one embodiment, the lead connector 27 is manufactured usingsilicone and the connector pin 28 is made of stainless steel, althoughother suitable materials could be used, as well. The insulated lead body13 utilizes a silicone-insulated alloy conductor material.

The housing 21 also contains a heart rate sensor 31 that is electricallyinterfaced with the logic and control circuitry, which receives thepatient's sensed heart rate as sensory inputs. The heart rate sensor 31monitors heart rate using an ECG-type electrode. Through the electrode,the patient's heart beat can be sensed by detecting ventriculardepolarization. In a further embodiment, a plurality of electrodes canbe used to sense voltage differentials between electrode pairs, whichcan be signal processed and combined into other cardiac physiologicalmeasures, for instance, P, QRS and T complexes. These cardiac artifactscan be used to derive other physiological measures and diagnose abnormalrhythm disorders and indicia, including sleep apnea, hypopnea index,dysautonomias (postural orthostatic tachycardia syndrome (POTS),vasovagal syncope, inappropriate sinus tachycardia (IST), and the like),and arrhythmia detection (atrial fibrillation, ventricular tachycardia,ventricular fibrillation, heart block, and so forth). Other direct andindirect uses of the heart rate sensor 31 are possible. In oneembodiment, the heart rate sensor 31 can be adjusted for sensitivity andis capable of detecting heart beats in the range of 20 to 240 bpm. Otherlevels and ranges of heart beat sensitivity are possible.

Prior to the initiation of titration and eventual therapeuticstimulation, the neurostimulator 12 remains idle, yet the time periodbetween implantation and therapy initiation provides an opportunity topassively monitor the patient's heart rate or other physiology,depending upon the capabilities of the neurostimulator 12. Ordinarily,the heart rate sensor 31 provides the sensed heart rate to the controland logic circuitry as sensory inputs, which can be stored as data inthe recordable memory 29. When sensed prior to therapy initiation, thesensory inputs of the heart rate sensor 31 can be used as a baselineheart rate, which reflects the pre-therapeutic condition of thepatient's cardiovascular drive. The sensed heart rate 29 can be chosenas either a direct measurement of heart rate, or statistically by takingan average, minimum, maximum, or mean heart rate over time. Other waysof determining a baseline heart rate through use of the heart ratesensor 29 or other sensory-input sources or devices integrated into theneurostimulator 12 are possible.

Once therapy has begun, the sensory inputs of the heart rate sensor 31serve as sensory-based therapy triggers to autonomously titrate VNSdelivery in light of the baseline heart rate. The logic and controlcircuitry can then determine whether the stimulation needs to beadjusted or inhibited. Alternatively, the baseline heart rate can beprogrammed into the neurostimulator 12 using, for instance, an externalprogrammer. Importantly, the baseline heart rate need not necessarily bebased on the patient's heart rate per se; non-heart rate ECGmeasurements, for example, could be used to derive the baseline heartrate and then programmed into the neurostimulator 12. Other ways ofdetermining a baseline heart rate from a source outside of theneurostimulator 12 are possible.

Therapy can be adjusted whenever the sensed heart rate falls out ofbounds relative to the baseline heart rate, such as outside of apredetermined heart rate range. A lower bound, stored in the recordablememory 29, can be set to indicate bradycardia or an asystolic heartcondition. The lower bound can be expressed as a ratio, percentile, orfunction, of the baseline heart rate, or as discrete independent(absolute) values with respect to the baseline heart rate. If the heartrate sensed by the heart rate sensor 31 falls below the lower bound onthe baseline heart rate, the neurostimulator 12 can be instructed,through the stimulation parameters, to suspend the triggering of thebi-directional action potentials altogether. Therapy can also beprogrammed to resume automatically after a fixed time period.Alternatively, the neurostimulator 12 can be instructed to down titratetherapy by gradually adjusting the stimulation parameters downwardsuntil the bradycardia or asystole are no longer present. Therapy canalso be programmed to gradually up titrate by adjusting the stimulationparameters upwards after first inhibiting stimulation for a fixed timeperiod. Both the down titration and the up titration can occur stepwise,where the changes in the stimulation parameters occur in smallincrements spread out over time, rather than all at once. VNS therapycan be titrated by adjusting the stored stimulation parameters,including output current, pulse width, and signal frequency, todifferent VNS therapeutic setting that are less intense (down titrate)or more intense (up titrate). An upper bound, stored in the recordablememory 29, can also be set to indicate insufficient therapy delivery.The upper bound can be expressed as a ratio, percentile, or function, ofthe baseline heart rate, or as discrete independent (absolute) valueswith respect to the baseline heart rate. If the heart rate sensed by theheart rate sensor 31 rises above an upper bound on the baseline heartrate, the neurostimulator 12 can be instructed, again through thestimulation parameters, to up titrate the triggering of thebi-directional action potentials and thereby lower heart rate.

The neurostimulator 12 is preferably interrogated prior to implantationand throughout the therapeutic period for checking proper operation,downloading recorded data, diagnosing problems, and programmingoperational parameters. FIG. 3 is a diagram showing an externalprogrammer 40 for use with the implantable neurostimulator 12 of FIG. 1.The external programmer 40 includes a healthcare provider-operableprogramming computer 41 and a programming wand 42. Generally, use of theexternal programmer 40 is restricted to healthcare providers, while morelimited manual control is provided to the patient through “magnet mode.”

In one embodiment, the programming computer 41 executes applicationsoftware specially designed to interrogate the neurostimulator 12. Theprogramming computer 41 interfaces to the programming wand 42 through astandardized wired data connection, including a serial data interface,for instance, an EIA RS-232 or USB serial port. Alternatively, theprogramming computer 41 and the programming wand 42 could interfacewirelessly. The programming wand 42 can be adapted from a Model 201Programming Wand, manufactured and sold by Cyberonics, Inc. Similarly,the application software can be adapted from the Model 250 ProgrammingSoftware suite, licensed by Cyberonics, Inc. Other configurations andcombinations of computer 41, programming wand 42, and applicationsoftware 45 are possible.

The programming computer 41 can be implemented using a general purposeprogrammable computer and can be a personal computer, laptop computer,netbook computer, handheld computer, or other form of computationaldevice. In one embodiment, the programming computer is a personaldigital assistant handheld computer operating under the Pocket-PC orWindows Mobile operating systems, licensed by Microsoft Corporation,Redmond, Wash., such as the Dell Axim X5 and X50 personal dataassistants, sold by Dell, Inc., Round Top, Tex., the HP Jornada personaldata assistant, sold by Hewlett-Packard Company, Palo Alto, Tex. Theprogramming computer 41 functions through those componentsconventionally found in such devices, including, for instance, a centralprocessing unit, volatile and persistent memory, touch-sensitivedisplay, control buttons, peripheral input and output ports, and networkinterface. The computer 41 operates under the control of the applicationsoftware 45, which is executed as program code as a series of process ormethod modules or steps by the programmed computer hardware. Otherassemblages or configurations of computer hardware, firmware, andsoftware are possible.

Operationally, the programming computer 41, when connected to aneurostimulator 12 through wireless telemetry using the programming wand42, can be used by a healthcare provider to remotely interrogate theneurostimulator 12 and modify stored stimulation parameters. Theprogramming wand 42 provides data conversion between the digital dataaccepted by and output from the programming computer and the radiofrequency signal format that is required for communication with theneurostimulator 12.

The healthcare provider operates the programming computer 41 through auser interface that includes a set of input controls 43 and a visualdisplay 44, which could be touch-sensitive, upon which to monitorprogress, view downloaded telemetry and recorded physiology, and reviewand modify programmable stimulation parameters. The telemetry caninclude reports on device history that provide patient identifier,implant date, model number, serial number, magnet activations, total ONtime, total operating time, manufacturing date, and device settings andstimulation statistics and on device diagnostics that include patientidentifier, model identifier, serial number, firmware build number,implant date, communication status, output current status, measuredcurrent delivered, lead impedance, and battery status. Other kinds oftelemetry or telemetry reports are possible.

During interrogation, the programming wand 42 is held by its handle 46and the bottom surface 47 of the programming wand 42 is placed on thepatient's chest over the location of the implanted neurostimulator 12. Aset of indicator lights 49 can assist with proper positioning of thewand and a set of input controls 48 enable the programming wand 42 to beoperated directly, rather than requiring the healthcare provider toawkwardly coordinate physical wand manipulation with control inputs viathe programming computer 41. The sending of programming instructions andreceipt of telemetry information occur wirelessly through radiofrequency signal interfacing. Other programming computer and programmingwand operations are possible.

Preferably, the helical electrodes 14 are placed over the cervical vagusnerve 15, 16 at the location below where the superior and inferiorcardiac branches separate from the cervical vagus nerve. FIG. 4 is adiagram showing the helical electrodes 14 provided as on the stimulationtherapy lead 13 of FIG. 2 in place on a vagus nerve 15, 16 in situ 50.Although described with reference to a specific manner and orientationof implantation, the specific surgical approach and implantation siteselection particulars may vary, depending upon physician discretion andpatient physical structure.

The helical electrodes 14 are positioned over the patient's vagus nerve61 oriented with the end of the helical electrodes 14 facing thepatient's head. At the distal end, the insulated electrical lead body 13is bifurcated into a pair of lead bodies 57, 58 that are connected to apair of electrodes proper 51, 52. The polarity of the electrodes 51, 52could be configured into a monopolar cathode, a proximal anode and adistal cathode, or a proximal cathode and a distal anode. In addition,an anchor tether 53 is fastened over the lead bodies 57, 58 thatmaintains the helical electrodes' position on the vagus nerve 61following implant. In one embodiment, the conductors of the electrodes51, 52 are manufactured using a platinum and iridium alloy, while thehelical materials of the electrodes 51, 52 and the anchor tether 53 area silicone elastomer.

During surgery, the electrodes 51, 52 and the anchor tether 53 arecoiled around the vagus nerve 61 proximal to the patient's head, eachwith the assistance of a pair of sutures 54, 55, 56, made of polyesteror other suitable material, which help the surgeon to spread apart therespective helices. The lead bodies 57, 58 of the electrodes 51, 52 areoriented distal to the patient's head and aligned parallel to each otherand to the vagus nerve 61. A strain relief bend 60 can be formed on thedistal end with the insulated electrical lead body 13 aligned parallelto the helical electrodes 14 and attached to the adjacent fascia by aplurality of tie-downs 59 a-b.

In one embodiment, the stimulation protocol calls for a six-weektitration period. During the first three-weeks, the surgical incisionsare allowed to heal and no VNS therapy occurs. During the secondthree-weeks, the neurostimulator 12 is first turned on and operationallytested. The impulse rate and intensity of the VNS is then graduallyincreased every three or four days until full therapeutic levels ofstimulation are achieved, or maximal patient tolerance is reached,whichever comes first. Patient tolerance can be gauged by physicaldiscomfort or pain, as well as based on presence of known VNSside-effects, such as ataxia, coughing, hoarseness, or dyspnea.

Therapeutically, the VNS is delivered through continual alternatingcycles of electrical pulses and rest (inhibition), which is specified tothe neurostimulator 12 through the stored stimulation parameters. Theneurostimulator 12 can operate either with or without an integratedheart rate sensor, such as respectively described in commonly-assignedU.S. patent application, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction with Leadless Heart Rate Monitoring,” Ser. No.______, filed on Dec. 7, 2011, pending, and U.S. patent application,entitled “Implantable Device for Providing Electrical Stimulation ofCervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction,”Ser. No. ______, filed on Dec. 7, 2011, pending, the disclosures ofwhich are incorporated by reference. Additionally, where an integratedleadless heart rate sensor is available, the neurostimulator 12 canprovide self-controlled titration, such as described incommonly-assigned U.S. patent application, entitled “Implantable Devicefor Providing Electrical Stimulation of Cervical Vagus Nerves forTreatment of Chronic Cardiac Dysfunction with Bounded Titration,” Ser.No. ______, filed on Dec. 7, 2011, pending, the disclosure of which isincorporated by reference.

A “duty cycle” is the percentage of time that the neurostimulator 12 isstimulating, that is, the percentage of ON times. The VNS can bedelivered with a periodic duty cycle in the range of around 5% to 30%.The selection of duty cycle is a tradeoff between competing medicalconsiderations. FIG. 5 is a graph 70 showing, by way of example, therelationship between the targeted therapeutic efficacy 73 and the extentof potential side effects 74 resulting from use of the implantableneurostimulator 12 of FIG. 1. The x-axis represents the duty cycle 71.The duty cycle is determined by dividing the stimulation time by the sumof the ON and OFF times of the neurostimulator 12. However, thestimulation time may also need to include ramp-up time and ramp-downtime, where the stimulation frequency exceeds a minimum threshold (asfurther described below with reference to FIG. 7). The y-axis representsphysiological response 72 to VNS therapy. The physiological response 72can be expressed quantitatively for a given duty cycle 71 as a functionof the targeted therapeutic efficacy 73 and the extent of potential sideeffects 74, as described infra. The maximum level of physiologicalresponse 72 (“max”) signifies the highest point of targeted therapeuticefficacy 73 or potential side effects 74.

Targeted therapeutic efficacy 73 and the extent of potential sideeffects 74 can be expressed as functions of duty cycle 71 andphysiological response 72. The targeted therapeutic efficacy 73represents the intended effectiveness of VNS in provoking a beneficialphysiological response for a given duty cycle and can be quantified byassigning values to the various acute and chronic factors thatcontribute to the physiological response 72 of the patient 10 due to thedelivery of therapeutic VNS. Acute factors that contribute to thetargeted therapeutic efficacy 73 include increase in heart ratevariability and coronary flow, reduction in cardiac workload throughvasodilation, and improvement in left ventricular relaxation. Chronicfactors that contribute to the targeted therapeutic efficacy 73 includedecreased parasympathetic activation and increased sympatheticactivation, as well as decreased negative cytokine production, increasedbaroreflex sensitivity, increased respiratory gas exchange efficiency,favorable gene expression, renin-angiotensin-aldosterone systemdown-regulation, anti-arrhythmic, anti-apoptotic, and ectopy-reducinganti-inflammatory effects. These contributing factors can be combined inany manner to express the relative level of targeted therapeuticefficacy 73, including weighting particular effects more heavily thanothers or applying statistical or numeric functions based directly on orderived from observed physiological changes. Empirically, targetedtherapeutic efficacy 73 steeply increases beginning at around a 5% dutycycle, and levels off in a plateau near the maximum level ofphysiological response at around a 30% duty cycle. Thereafter, targetedtherapeutic efficacy 73 begins decreasing at around a 50% duty cycle andcontinues in a plateau near a 25% physiological response through themaximum 100% duty cycle.

The extent of potential side effects 74 represents the occurrence of apossible physiological effect, either adverse or therapeutic, that issecondary to the benefit intended, which presents in the patient 10 inresponse to VNS and can be quantified by assigning values to thephysiological effects presented due to the delivery of therapeutic VNS.The degree to which a patient 10 may be prone to exhibit side effectsdepends in large part upon the patient's condition, including degree ofcardiac dysfunction, both acute and chronic, any comobidities, priorheart problems, family history, general health, and similarconsiderations. As well, the type and severity of a side effect ispatient-dependent. For VNS in general, the more common surgical- andstimulation-related adverse side effects include infection, asystole,bradycardia, syncope, abnormal thinking, aspiration pneumonia, devicesite reaction, acute renal failure, nerve paralysis, hypesthesia, facialparesis, vocal cord paralysis, facial paralysis, hemidiaphragmparalysis, recurrent laryngeal injury, urinary retention, and low gradefever. The more common non-adverse side effects include hoarseness(voice alteration), increased coughing, pharyngitis, paresthesia,dyspnea, dyspepsia, nausea, and laryngismus. Less common side effects,including adverse events, include ataxia, hypesthesia, increasecoughing, insomnia, muscle movement or twitching associated withstimulation, nausea, pain, paresthesia, pharyngitis, vomiting,aspiration, blood clotting, choking sensation, nerve damage, vasculaturedamage, device migration or extrusion, dizziness, dysphagia, duodenal orgastric ulcer, ear pain, face flushing, facial paralysis or paresis,implant rejection, fibrous tissue formation, fluid pocket formation,hiccupping, incision site pain, irritability, laryngeal irritation,hemidiaphragm paralysis, vocal cord paralysis, muscle pain, neck pain,painful or irregular stimulation, seroma, skin or tissue reaction,stomach discomfort, tinnitus, tooth pain, unusual scarring at incisionsite, vagus nerve paralysis, weight change, worsening of asthma orbronchitis. These quantified physiological effects can be combined inany manner to express the relative level of extent of potential sideeffects 74, including weighting particular effects more heavily thanothers or applying statistical or numeric functions based directly on orderived from observed physiological changes. Empirically, the extent ofpotential side effects 74 is initially low until around a 25% dutycycle, at which point the potential begins to steeply increase. Theextent of potential side effects 74 levels off in a plateau near themaximum level of physiological response at around a 50% duty cyclethrough the maximum 100% duty cycle.

The intersection 75 of the targeted therapeutic efficacy 73 and theextent of potential side effects 74 represents the optimal duty cyclerange for VNS. FIG. 6 is a graph 80 showing, by way of example, theoptimal duty cycle range 83 based on the intersection 75 depicted inFIG. 5. The x-axis represents the duty cycle 81 as a percentage ofstimulation time over inhibition time. The y-axis represents thedesirability 82 of operating the neurostimulator 12 at a given dutycycle 81. The optimal duty range 83 is a function 84 of the intersection74 of the targeted therapeutic efficacy 73 and the extent of potentialside effects 74. The desirability 82 can be expressed quantitatively fora given duty cycle 81 as a function of the values of the targetedtherapeutic efficacy 73 and the extent of potential side effects 74 attheir point of intersection in the graph 70 of FIG. 5. The maximum levelof desirability 82 (“max”) signifies a tradeoff that occurs at the pointof highest targeted therapeutic efficacy 73 in light of lowest potentialside effects 74 and that point will typically be found within the rangeof a 5% to 30% duty cycle 81. Other expressions of duty cycles andrelated factors are possible.

The neurostimulator 12 delivers VNS according to stored stimulationparameters, which are programmed using an external programmer 40 (shownin FIG. 3). Each stimulation parameter can be independently programmedto define the characteristics of the cycles of therapeutic stimulationand inhibition to ensure optimal stimulation for a patient 10. Theprogrammable stimulation parameters affecting stimulation include outputcurrent, signal frequency, pulse width, signal ON time, signal OFF time,magnet activation (for VNS specifically triggered by “magnet mode”),“AutoStim” activation (delivered upon detection of a biological signalindicative of physiological conditions, such as bradycardia orasystole), and reset parameters. Other programmable parameters arepossible.

VNS is delivered in alternating cycles of stimuli application andstimuli inhibition that are tuned to both efferently activate theheart's intrinsic nervous system and heart tissue and afferentlyactivate the patient's central reflexes. FIG. 7 is a timing diagramshowing, by way of example, a stimulation cycle and an inhibition cycleof VNS 90 as provided by implantable neurostimulator 12 of FIG. 1. Thestimulation parameters enable the electrical stimulation pulse output bythe neurostimulator 12 to be varied by both amplitude (output current96) and duration (pulse width 94). The number of output pulses deliveredper second determines the signal frequency 93. In one embodiment, apulse width in the range of 100 to 250 μsec delivers between 0.02 and 50mA of output current at a signal frequency of about 20 Hz, althoughother therapeutic values could be used as appropriate.

In the simplest case, the stimulation time is the time period duringwhich the neurostimulator 12 is ON and delivering pulses of stimulation.The OFF time 95 is always the time period occurring in-betweenstimulation times 91 during which the neurostimulator 12 is OFF andinhibited from delivering stimulation. In one embodiment, theneurostimulator 12 implements a ramp-up time 97 and a ramp-down time 98that respectively precede and follow the ON time 92 during which theneurostimulator 12 is ON and delivering pulses of stimulation at thefull output current 96. The ramp-up time 97 and ramp-down time 98 areused when the stimulation frequency is at least 10 Hz, although otherminimum thresholds could be used, and both times last two seconds,although other time periods could also be used. The ramp-up time 97 andramp-down time 98 allow the strength of the output current 96 of eachoutput pulse to be gradually increased and decreased, thereby avoidingunnecessary trauma to the vagus nerve due to sudden delivery orinhibition of stimulation at full strength.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope.

1. A vagus nerve neurostimulator for evaluating autonomic cardiovasculardrive, comprising: an implantable neurostimulator comprising: a pulsegenerator configured to deliver electrical therapeutic stimulation tunedto restore autonomic balance through continuously-cycling, intermittentand periodic electrical pulses simultaneously delivered at a periodicduty cycle in a range between 5% and 30%, at an intensity that avoidsacute physiological side effects and with an unchanging cycle nottriggered by physiological markers in both afferent and efferentdirections of a cervical vagus nerve through a pair of helicalelectrodes via an electrically coupled nerve stimulation therapy lead;and a leadless heart rate sensor configured to continually monitor heartrate against a stored baseline heart rate.
 2. A neurostimulatoraccording to claim 1, wherein the pulse generator is further configuredto suspend the electrical therapeutic stimulation for a fixed period oftime in response to the monitored heart rate falling below a storedlower bound, after which the electrical therapeutic stimulation resumes.3. A neurostimulator according to claim 1, wherein the pulse generatoris further configured to gradually down titrate the electricaltherapeutic stimulation in response to the monitored heart rate fallingbelow a stored lower bound.
 4. A neurostimulator according to claim 3,wherein the pulse generator is further configured to suspend theelectrical therapeutic stimulation for a fixed period of time andgradually up titrate the electrical therapeutic stimulation after thedown titration.
 5. A neurostimulator according to claim 1, wherein thepulse generator is further configured to gradually up titrate theelectrical therapeutic stimulation in response to the monitored heartrate rising above a stored upper bound.
 6. An implantable device forevaluating autonomic cardiovascular drive, comprising: an implantableneurostimulator comprising a pulse generator configured to deliverelectrical therapeutic stimulation tuned to restore autonomic balance atan intensity that avoids acute physiological side effects and with anunchanging cycle not triggered by physiological markers throughcontinuously-cycling, intermittent and periodic electrical pulsessimultaneously delivered at a periodic duty cycle in a range between 5%and 30% in both afferent and efferent directions of a cervical vagusnerve in continuous alternating cycles of stimuli application andstimuli inhibition; a cervical vagus nerve stimulation therapy leadelectrically coupled to the pulse generator and terminated by a pair ofhelical electrodes through which the therapeutic electrical stimulationis delivered to the cervical vagus nerve; and an integrated leadlessheart rate sensor configured to continually monitor heart rate against abaseline heart rate stored in a memory in the pulse generator.
 7. Animplantable device according to claim 6, wherein the pulse generator isfurther configured to suspend the therapeutic electrical stimulation fora fixed period of time in response to the monitored heart rate fallingbelow a lower bound stored in the memory that is indicative of at leastone of bradycardia and asystole, after which the therapeutic electricalstimulation resumes.
 8. An implantable device according to claim 6,wherein the pulse generator is further configured to gradually downtitrate the therapeutic electrical stimulation in response to themonitored heart rate falling below a lower bound stored in the memorythat is indicative of at least one of bradycardia and asystole.
 9. Animplantable device according to claim 8, wherein the pulse generator isfurther configured to suspend the therapeutic electrical stimulation fora fixed period of time and gradually up titrate the therapeuticelectrical stimulation after the down titration.
 10. An implantabledevice according to claim 6, wherein the pulse generator is furtherconfigured to gradually up titrate the therapeutic electricalstimulation in response to the monitored heart rate rising above anupper bound stored in the memory that is indicative of insufficienttherapy delivery.
 11. An implantable device according to claim 6,further comprising: a connector pin and an insulated electrical leadbody that further comprise the therapy lead and which are electricallyconnected to the helical electrodes; and an electrical receptaclecomprised on an outer surface of the neurostimulator into which theconnector pin is securely and electrically connected to the pulsegenerator.
 12. An implantable device for evaluating autonomiccardiovascular drive in a patient suffering from chronic cardiacdysfunction, comprising: a cervical vagus nerve stimulation therapylead, comprising: a pair of helical electrodes configured to conform toan outer diameter of a cervical vagus nerve sheath of a patient; and aset of connector pins electrically connected to the helical electrodesby an insulated electrical lead body; and a neurostimulator powered by aprimary battery and enclosed in a hermetically sealed housing, furthercomprising: an electrical receptacle comprised on an outer surface ofthe housing into which the connector pins are securely and electricallycoupled; a pulse generator configured to therapeutically stimulate thecervical vagus nerve through the helical electrodes in alternatingcycles of stimuli application and stimuli inhibition that are tuned torestore autonomic balance at an intensity that avoids acutephysiological side effects and with an unchanging cycle not triggered byphysiological markers through continuously-cycling, intermittent andperiodic electrical pulses simultaneously delivered at a periodic dutycycle in a range between 5% and 30% in both afferent and efferentdirections of the vagus nerve to both efferently activate the heart'sintrinsic nervous system and afferently activate the patient's centralreflexes by triggering bi-directional action potentials; a recordablememory within which is stored a baseline heart rate for the patientprior to stimulation therapy initiation; and an integrated leadlessheart rate sensor configured to continually monitor the patient's heartrate in light of the baseline heart rate.
 13. An implantable deviceaccording to claim 12, wherein the integrated leadless heart rate sensoris further configured to sense the baseline heart rate during a timeperiod prior to stimulation therapy initiation.
 14. An implantabledevice according to claim 12, wherein the integrated leadless heart ratesensor is further configured to determine the baseline heart rate as atleast one of a direct measurement of heart rate, an average heart rateover time, a minimum heart rate over time, a maximum heart rate overtime, and a mean heart rate over time.
 15. An implantable deviceaccording to claim 12, wherein the baseline heart rate is programmedinto the recordable memory prior to stimulation therapy initiation. 16.An implantable device according to claim 12, wherein the baseline heartrate is determined by ECG measurements other than the patient's heartrate prior to stimulation therapy initiation and thereafter programmedinto the recordable memory.
 17. An implantable device according to claim12, wherein a lower bound, which is indicative of at least one ofbradycardia and asystole, defined below the baseline heart rate, isstored in the recordable memory and the pulse generator is furtherconfigured to suspend the triggering of the bi-directional actionpotentials for a fixed period of time in response to the sensed heartrate falling below the lower bound, after which the triggering of thebi-directional action potentials resumes.
 18. An implantable deviceaccording to claim 17, wherein the lower bound is expressed as at leastone of a ratio, a percentile, a function, and discrete independentvalues with respect to the baseline heart rate.
 19. An implantabledevice according to claim 12, wherein a lower bound, which is indicativeof at least one of bradycardia and asystole, defined below the baselineheart rate, is stored in the recordable memory and the pulse generatoris further configured to gradually down titrate the triggering of thebi-directional action potentials in response to the sensed heart ratefalling below the lower bound.
 20. An implantable device according toclaim 19, wherein the pulse generator is further configured to suspendthe triggering of the bi-directional action potentials for a fixedperiod of time and gradually up titrate the triggering of thebi-directional action potentials after the down titration.
 21. Animplantable device according to claim 12, wherein an upper bound, whichis indicative of insufficient therapy delivery, defined above thebaseline heart rate, is stored in the recordable memory and the pulsegenerator is further configured to gradually up titrate the triggeringof the bi-directional action potentials in response to the sensed heartrate rising above the upper bound.
 22. An implantable device accordingto claim 21, wherein the upper bound is expressed as at least one of aratio, a percentile, a function, and discrete independent values withrespect to the baseline heart rate.